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Abstract

OBJECTIVES The purpose of this study is to determine the spectrum of cardiac mutations among a cohort of unrelated patients referred for long QT syndrome (LQTS) commercial genetic testing and to compare the findings with reports derived from research laboratories.

METHODS A comprehensive open reading frame/splice site mutational analysis of all 60 translated exons in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed using DNA sequencing for 524 unrelated patients referred to Clinical Data (formerly Genaissance Pharmaceuticals) for LQTS testing between August 2004 and May 2006.

RESULTS Overall, 191 (36%) index cases (126 female) had a positive test: LQT1 (84, 44%), LQT2 (70, 37%), LQT3 (21, 11%), LQT5 (5, 2.6%), LQT6 (0), and complex multiples (11, 5.8%). 159 distinct mutations were identified: 69 in KCNQ1, 60 in KCNH2, 26 in SCN5A, and 4 in KCNE1. None of these mutations were seen in over 2600 reference alleles. The majority (74%) were missense mutations. Compared with two large studies that each found a 59% prevalence of novel mutations, only 67 (42%; p < 0.001 vs. each) of the mutations were novel: 20 in KCNQ1, 28 in KCNH2, 17 in SCN5A, and 2 in KCNE1.

CONCLUSIONS During the decade (1995 – 2005) of research-based genetic testing, over 500 LQTS-associated mutations were discovered. The past two years of clinical LQTS testing has increased the compendium of unique mutations by 67, and the approximate number of mutations discovered in cases of LQTS is now over 650. Our results indicate that the rate of novel mutations is on the decline. We estimate that mutation saturation within these five genes will exceed 1000 distinct mutations. The frequency of positive genetic test results (36%) is lower than observed from the largest research based cohort of unrelated patients (50%) or the expected yield of 75% when the clinical diagnosis of LQTS is high probability, probably reflecting the referral case mix.